A functional selectivity mechanism at the serotonin-2A GPCR involves ligand-dependent conformations of intracellular loop 2

Perez-Aguilar, Jose Manuel; Shan, Jufang; LeVine, Michael V.; Khelashvili, George; Weinstein, Harel

doi:10.1021/ja508394x

A functional selectivity mechanism at the serotonin-2A GPCR involves ligand-dependent conformations of intracellular loop 2

Journal Article · Tue Oct 14 00:00:00 EDT 2014 · Journal of the American Chemical Society

DOI:https://doi.org/10.1021/ja508394x· OSTI ID:1345813

Perez-Aguilar, Jose Manuel ^[1]; Shan, Jufang ^[2]; LeVine, Michael V. ^[2]; Khelashvili, George ^[2]; Weinstein, Harel ^[2]

Weill Medical College of Cornell Univ., New York, NY (United States); Office of Scientific and Technical Information (OSTI)
Weill Medical College of Cornell Univ., New York, NY (United States)

With recent progress in determination of G protein-coupled receptor (GPCR) structure with crystallography, a variety of other experimental approaches (e.g., NMR spectroscopy, fluorescent-based assays, mass spectrometry techniques) are also being used to characterize state-specific and ligand-specific conformational states. MD simulations offer a powerful complementary approach to elucidate the dynamic features associated with ligand-specific GPCR conformations. To shed light on the conformational elements and dynamics of the important aspect of GPCR functional selectivity, we carried out unbiased microsecond-length MD simulations of the human serotonin 2A receptor (5-HT_2AR) in the absence of ligand and bound to four distinct serotonergic agonists. The 5-HT_2AR is a suitable system to study the structural features involved in the ligand-dependent conformational heterogeneity of GPCRs because it is well-characterized experimentally and exhibits a strong agonist-specific phenotype in that some 5-HT_2AR agonists induce LSD-like hallucinations, while others lack this psychoactive property entirely. Here we report evidence for structural and dynamic differences in 5-HT_2AR interacting with such pharmacologically distinct ligands, hallucinogens, and nonhallucinogens obtained from all-atom MD simulations. Differential ligand binding contacts were identified for structurally similar hallucinogens and nonhallucinogens and found to correspond to different conformations in the intracellular loop 2 (ICL2). From the different ICL2 conformations, functional selective phenotypes are suggested through effects on dimerization and/or distinct direct interaction with effector proteins. Lastly, the findings are presented in the context of currently proposed hallucinogenesis mechanisms, and ICL2 is proposed as a fine-tuning selective switch that can differentiates modes of 5-HT_2AR activation.

View Accepted Manuscript (DOE)

Research Organization:: Weill Medical College of Cornell Univ., New York, NY (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1345813

Journal Information:: Journal of the American Chemical Society, Journal Name: Journal of the American Chemical Society Journal Issue: 45 Vol. 136; ISSN 0002-7863

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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